The coronary arteries supply the myocardium, or muscle of the heart with oxygen and nutrients. Over time the coronary arteries can become blocked with cholesterol and other material known as plaque. Coronary artery disease results from this buildup of plaque within the walls of the coronary arteries. Excessive plaque build-up can lead to diminished blood flow through the coronary arteries and low blood flow to the myocardium leading to chest pain, ischemia, and heart attack. Coronary artery disease (CAD) can also weaken the heart muscle and contribute to heart failure, a condition where the heart's efficiency as a pump is compromised. This state can lead to electrical disorders of the heart that increase the possibility for sudden cardiac death. Coronary artery disease is the leading cause of death for both men and women in the United States. CAD affects 17.6 million Americans and results in nearly half a million deaths per year. Despite access to sophisticated diagnostic imaging tests at a cost of $6.3 billion per year, over 1,000,000 US patients are referred to unnecessary invasive catheterization procedures exposing patients to inherent risks and a staggering $8 B financial burden to the US healthcare system.
There are several different diagnostics that are currently used to assess coronary artery disease and its severity. Non-invasive tests can include electrocardiograms, biomarker evaluations from blood tests, treadmill tests, echocardiography, single positron emission computed tomography (SPECT), and positron emission tomography (PET). Unfortunately, these non-invasive tests do not provide data related to the size of a coronary lesion or its specific effect on coronary blood flow, pressure gradients and fractional flow reserve.
Quantitative coronary angiography (QCA) is a well-established invasive method for visualizing and quantifying the size of an arterial lesion such as those associated with coronary artery disease. In this method, a radiopaque contrast agent is injected into the blood and an x-ray scan movie is acquired when the contrast agent has traveled into the coronary arteries. Clinicians can use this information to visually examine and to quantify the degree of obstruction. An area obstruction of greater than 70% has traditionally been considered flow-limiting and a candidate for percutaneous coronary intervention (PCI) (also known as coronary angioplasty).
While the above procedure can be used to visualize and quantify the size of the lesion or the degree of obstruction, it does not necessarily correlate to the functional significance of the lesion, i.e. the degree to which the lesion affect the rate of flow of blood through the artery. Therefore, additional assessments have been developed to determine functional significance of coronary artery lesions. In this regard catheter measured coronary flow velocity (CFV), pressure gradient (PG) i.e. the pressure difference across various arterial segments, coronary flow reserve (CFR), and fractional flow reserve (FFR) are the gold standards for assessment of the functional significance of coronary artery stenosis. These metrics are currently determined using diagnostic cardiac catheterization, an invasive procedure in which a catheter is inserted into a peripheral artery (for instance in a patient's leg) and threaded through the vasculature to the relevant areas of the coronary arteries. FFR is determined by calculating the ratio of the mean blood pressure downstream from a lesion divided by the mean blood pressure upstream from the same lesion. These pressures are measured by inserting a pressure wire into the patient during the diagnostic cardiac catheterization procedure. While this procedure provides an accurate measure of FFR for determining the functional severity of the coronary stenosis, it incurs the risk and cost of an invasive procedure.
Advances in multi-detector computed tomography (CT) technology now allows noninvasive access to several important factors in regards to coronary event risk: the overall coronary arterial plaque burden, the severity of coronary arterial stenoses, the location and consistency of plaque, and plaque configuration. While anatomic information on CAD by CT is important and has been shown to correlate with patient outcomes, there are other important determinants of patient outcome with CHD including the degree of epicardial blood flow reduction and the extent and severity of provocable myocardial ischemia. CT allows the assessment of coronary anatomy, coronary blood flow, and myocardial perfusion and thus, is uniquely positioned to acquire comprehensive information to guide the evaluation and management of patients with suspected CHD.
While coronary CTA has been shown to be an accurate test to diagnose the presence of coronary atherosclerosis and percent stenosis it has been shown to poorly predict myocardial ischemia compared to invasive and non-invasive standards. Compared to positron emission tomography, a 50% stenosis by CTA has a positive predictive value for myocardial ischemia of 26% a finding that has been reproduced in a number of studies. Compared to FFR, the invasive gold standard for determining the physiologic significance of a stenosis, percent stenosis by CTA shows only a moderate overall correlation (r=0.55) and no significant correlation with lesions ≦10 mm in length (r=0.16).
FFR can also be estimated based on a highly complex computational fluid dynamics (CFD) modeling in CT derived, patient-specific coronary artery models. This approach by HeartFlow Inc. and called FFRCT™ requires a high level of sophistication, is computationally intensive, and generally requires that patient-specific data be transmitted out of the hospital environment to a third party vendor. It is also expensive and can take several days to obtain results. Additionally, recent data testing this approach to predict actual FFR in a multicenter trial have been disappointing. For instance, the study did not meet its pre-specified primary endpoint, which was diagnostic accuracy of >70% of the lower bound of the one-sided 95% CI. One factor contributing to the computational complexity as well as the reduced accuracy of this approach is the lack of precise boundary and input conditions for velocity/flow rate for the artery of interest. An attempts to overcome this is made in FFRCT™ by combining a variety of information including patient-specific ventricular mass, resting coronary flow from population derived relationships and population derived measures of coronary resistances. The above information is combined with physiologic data such as blood pressure, heart rate and computational fluid dynamic (CFD) modeling of the ascending aorta and all the major coronary vessels. This CFD model is also connected with the rest of the circulatory system via lumped-element (or “windkessel”) models which contain a number of population derived parameters. However, this approach necessitates the use of ad-hoc parameters and generic (non-patient-specific) factors which can reduce the accuracy of the computed FFR. The quality of the CFD solution is highly sensitive to the computational grid that is employed and the need to generate a grid over the large section of the circulatory system (ascending aorta and coronary arteries) also introduces an additional source of inaccuracy and uncertainty in the results from the CFD calculation.
It would therefore be advantageous to provide an alternative non-invasive CT based method for assessing hemodynamic parameters such as determining the CFV, PG, CFR, and/or FFR for a given patient's coronary arteries. If such a method is computationally simple and relatively inexpensive, it could be implemented in the scanner or locally on a computer at the scanning facility, and the results made available within a relatively short time (order of minutes) after the completion of the scan. This would also allow the radiologist/clinician to interact in near-real time with the analysis tool. Such an approach would fundamentally change the practice of clinical cardiology and allow clinicians to accurately and rapidly identify specific vessels that are resulting in a reduction in the blood flow to the myocardium.